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The role of synaptic ion channels in synaptic plasticity
Giannis Voglis & Nektarios Tavernarakis+
Institute of Molecular Biology and Biotechnology, Heraklion, Crete, Greece
The nervous system receives a large amount of information about
the environment through elaborate sensory routes. Processing and
integration of these wide-ranging inputs often results in long-term
behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the
capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying
this process. Repeated neural activity generates physiological
changes in the nervous system that ultimately modulate neuronal
communication through synaptic transmission. Recent studies
implicate both presynaptic and postsynaptic ion channels in the
process of synapse strength modulation. Here, we review the role of
synaptic ion channels in learning and memory, and discuss the
implications and significance of these findings towards deciphering
the molecular biology of learning and memory.
Keywords: acetylcholine; GABA; long-term potentiation;
neurotransmitter; NMDA; synaptic transmission
EMBO reports (2006) 7, 1104–1110 . doi:10.1038/sj.embor.7400830
Introduction
Information storage and retrieval by the nervous system involves
physical alterations in the neuronal substrate that modulate neuron
activity and communication. These alterations can take many
forms; for example, structural modifications include the re-wiring
of neuronal networks, which can involve synapses being formed
between previously unconnected neurons and existing connections being strengthened by the addition of new synapses.
Moreover, information processing induces elaborate changes in the
function of individual neurons, such as the adjustment of neuronal
excitability and the regulation of synaptic strength (Nicoll &
Schmitz, 2005; Zucker & Regehr, 2002).
Synaptic strength, or synaptic weight, is a measure of synapse efficacy in relaying a signal from the presynaptic to the postsynaptic neuron. More than 50 years ago, Donald Hebb postulated that modulation of synaptic weight underlies learning and memory
phenomena (reviewed in Turrigiano & Nelson, 2000). His model,
also known as the ‘Hebb synapse’, suggests that synapses between
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology,
Vassilika Vouton, PO Box 1385, Heraklion 71110, Crete, Greece
+
Corresponding author: Tel: +30 2810 39 1066; Fax: +30 2810 39 1067;
E-mail: [email protected]
Submitted 11 April 2006; accepted 22 August 2006
1 1 0 4 EMBO reports VOL 7 | NO 11 | 2006
neurons are strengthened by concerted pre- and postsynaptic
neuronal activity. Conversely, synapses are weakened by noncoincidental neuronal firing. An integral component of this model is
synaptic plasticity, which is the capacity of a synapse to adapt to overall neuronal activity. Indeed, a wealth of experimental data supports
the idea that synaptic transmission can be potentiated or depressed,
depending on neuronal stimulation. Long-term potentiation and
depression (LTP and LTD, respectively) have been associated with
learning and memory models in many organisms (Bear & Malenka,
1994; Siegelbaum & Kandel, 1991; Xu & Kang, 2005). But how is
synapse reinforcement or attenuation achieved? Many molecular
mechanisms have been implicated in the regulation of synaptic transmission (Debanne et al, 2003; Frick & Johnston, 2005; Magee &
Johnston, 2005; Malenka & Bear, 2004). Several recent, elegant studies have shown that specific ion channels, localized at synapses,
facilitate synaptic plasticity phenomena (Table 1). In this review, we
aim to provide an entry point for further exploration of the vast literature on the mechanisms underlying learning and memory, focusing
on the involvement of synaptic ion channels in shaping synaptic
communication and plasticity.
Neurotransmitter receptor ion channels
According to Hebb’s conjecture, synaptic plasticity is manifested by
experience-induced modifications in synaptic transmission (Cline,
2003). The Hebbian learning rule, formulated on the basis of this inference, dictates that such synaptic modifications depend on the excitation states of both the pre- and postsynaptic neuron. How is this type
of learning implemented at the synapse? Numerous studies in both
vertebrates and invertebrates have revealed that receptors for neurotransmitters have key roles in this process (Luscher et al, 2000).
Neurotransmitter receptors can be classified into two categories:
G-protein-coupled (metabotropic) receptors and ionotropic receptors.
The binding of neurotransmitters to G-protein-coupled receptors triggers a series of signal transduction cascades at postsynaptic neurons.
Ionotropic receptors are specialized synaptic ion channels, which are
gated by the binding of specific neurotransmitters. The influx of ions
that occurs on activation of ionotropic receptors alters the polarization
state of the postsynaptic neuron, and action potentials are fired if a
depolarization threshold is exceeded.
Ionotropic glutamate receptors. L-glutamate is the main excitatory
neurotransmitter in the mammalian nervous system and is detected
at postsynaptic terminals by both G-protein-coupled and ionotropic
glutamate receptors (GluRs). GluRs are subdivided into three main
©2006 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION
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Ion channels at the synapse
G. Voglis & N. Tavernarakis
Table 1 | Synaptic ion channels modulating learning and memory. Channel properties that are relevant to synaptic plasticity phenomena are listed
Ion channel
NMDA receptor
Ligand, activator
L-Glutamate, NMDA
Conducted ion Relevant expression
Na+, Ca2+
Hippocampus
Synaptic localization Reference
Presynaptic,
postsynaptic
Daw et al, 1993; Humeau et al, 2003
AMPA receptor L-Glutamate, AMPA
Na+, K+
Hippocampus, cerebellum
Presynaptic,
postsynaptic
Lee et al, 2003; Lu et al, 2001
Kainate receptor L-Glutamate, kainate
Na+, Ca2+, K+
Hippocampus,
Presynaptic,
thalamocortical system
postsynaptic
Lauri et al, 2003
nAch receptor
Acetylcholine, nicotine Na+, K+, Ca2+
Hippocampus
Presynaptic,
postsynaptic
Ji et al, 2001
–
GABA receptor γ-aminobutyric acid
Cl
Hippocampus
Postsynaptic
Collinson et al, 2002
L-type VGCC
Membrane potential
Ca2+
Amygdala, hippocampus
Presynaptic,
postsynaptic
Shinnick-Gallagher et al, 2003
P/Q-type VGCC Membrane potential
Ca2+
Hippocampus, Purkinje cells Presynaptic
Wu et al, 1999
R-type VGCC
Membrane potential
Ca2+
Hippocampus
Presynaptic
Wu et al, 1998
BK channel
Ca2+
K+
Hippocampus, Purkinje cells Presynaptic
Raffaelli et al, 2004; Sausbier et al, 2004
SK channel
Ca2+
K+
Amygdala, hippocampus
Postsynaptic
Hammond et al, 2006
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; BK, large conductance calcium-gated potassium channel; GABA, γ-aminobutyric acid;
LTP, long-term potentiation; nAChR, nicotinic acetylcholine receptor; NMDA, N-methyl-D-aspartate; SK, small conductance calcium-gated potassium
channel; VGCC, voltage-gated calcium channel.
types: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA), N-methyl-D-aspartic acid (NMDA), and kainate. All three
bind glutamate with high affinity and have varying preferences for
other glutamate agonists, including AMPA, NMDA and kainate
(Erreger et al, 2004). AMPA receptors are tetrameric ion channels
that principally conduct sodium and potassium ions, although,
depending on their subunit composition, they can also be permeable to calcium (Gouaux, 2004). NMDA receptors are tetrameric
non-selective cation channels that, in addition to ligand gating,
show voltage dependence (Dingledine et al, 1999). NMDA receptor
opening requires both glutamate binding and the relief of a magnesium ion (Mg2+) block, which involves depolarization of the postsynaptic membrane. Kainate receptors are pentameric ion channels
that are mostly permeable to sodium and potassium, with a low
conductivity for calcium (Ferrer-Montiel & Montal, 1996).
An overwhelming number of studies implicate all three GluR
types in learning and memory (Fig 1; Bliss & Collingridge, 1993).
Furthermore, GluRs have been associated with various types of
memory including long- and short-term memory, memory consolidation, spatial memory, episodic memory and contextual fear memory (Tsien et al, 1996; Zhao et al, 2005). AMPA and NMDA receptors
synergize at postsynaptic terminals to facilitate various forms of
synaptic plasticity. Sustained activation of AMPA receptors by a
series of impulses arriving at presynaptic terminals initiates depolarization of the postsynaptic membrane and removes the Mg2+ ions
that are obstructing NMDA receptors (Daw et al, 1993). Therefore, in
agreement with the Hebb hypothesis, simultaneous excitation of preand postsynaptic neurons facilitates gating of NMDA channels and
strengthens the synapse. An important feature of the NMDA channel,
which is particularly relevant to synaptic plasticity, is its high permeability to calcium; in turn, calcium, which is a central messenger
molecule, orchestrates a battery of signalling pathways and responses
that collectively elicit synaptic modification.
NMDA receptors participate in both the induction and the
maintenance of LTP at postsynaptic hippocampal neurons. The
induction of LTP involves opening NMDA channels to calcium
©2006 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION
through the removal of the Mg2+ block, whereas LTP maintenance
is achieved by subsequent calcium-induced synapse alterations.
One such modification engages AMPA receptor gating and transport. Signalling through the AMPA receptor is dynamically modulated by two principal mechanisms: direct phosphorylation of
receptor subunits, and changes in the density of receptors at the
postsynaptic membrane. During LTP in hippocampal pyramidal
neurons, many kinases become activated including the
calcium/calmodulin-dependent kinase II (CaMKII) and protein
kinase A. These kinases respond to calcium transients and mediate
the induction of enhanced synaptic transmission by phosphorylating
specific AMPA receptor subunits (Lee et al, 2003). Phosphorylation
increases the open probability of the receptor in LTP, whereas
dephosphorylation is induced during LTD. AMPA receptor transport to and from the synapse is also important for synaptic plasticity. The concentration of AMPA receptors at the synapse increases
after the induction of LTP, whereas it drops during LTD (Lu et al,
2001). Insertion of AMPA receptors at the postsynaptic membrane
and their turnover is regulated through the phosphorylation of specific receptor subunits triggered by synaptic calcium fluctuations
(Malenka, 2003; Malinow & Malenka, 2002).
This common theme has emerged by dissecting the involvement of NMDA receptors in synaptic plasticity, but in reality the
situation is far more complex with many forms of LTP induced by
diverse inputs in different neurons. One intriguing case is that of
activity-dependent synaptic plasticity, stimulated by presynaptic
NMDA channels. In the lateral nucleus of the amygdala, neuronal
activity induces LTP, which requires NMDA receptors but is independent of postsynaptic activity (Humeau et al, 2003). These
observations suggest that NMDA function, which is essential for
learning and memory, is not limited to postsynaptic terminals.
Synaptic plasticity in the hippocampus does not always depend
on NMDA receptors. The synapses between mossy fibres of the
hippocampal dendate gyrus and CA3 neurons show a distinctive
morphology with many sites for glutamate release, each of which
has a corresponding postsynaptic bundle of glutamate receptors. At
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Ion channels at the synapse
G. Voglis & N. Tavernarakis
Presynaptic neuron
Depolarization
Synaptic
vesicle
Synaptic
cleft
Na+
Glutamate
Na+
Kainate
receptor
Mg2+
release
Ca2+
Ca2+
Na+
AMPA
receptor
NMDA
receptor
P
P
Depolarization
AMPA
receptor
trafficking
Calcium influx
PKA
cAMP
P
Adenyl
cyclase
PKC
MAPK
CREB
Ca2+ Calmodulin
CaMKII
Postsynaptic neuron
Protein synthesis
Fig 1 | Glutamate receptors and synaptic plasticity. The arrival of a series of
impulses at the presynaptic terminal triggers the release of glutamate, which
binds to glutamate receptors at the postsynaptic membrane. On activation,
AMPA and kainate receptors conduct sodium ions, which initiate
postsynaptic depolarization. Membrane potential changes initiate the release
of magnesium ions that block NMDA receptors. Calcium influx through
NMDA channels sets off a chain of events that establish long-term
potentiation. Kainate receptors at the presynaptic end also seem to facilitate
synaptic transmission at specific synapses by augmenting neurotransmitter
release. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate;
CaMKII, calcium/calmodulin-dependent kinase II; CREB, cAMP response
element binding protein; MAPK, mitogen-activated protein kinase; NMDA,
N-methyl-D-aspartate; PKA, protein kinase A; PKC, protein kinase C.
this synapse, LTP is NMDA-receptor-independent and requires calcium influx through presynaptic kainate receptors (Lauri et al,
2003). Although the mechanism responsible for this type of synaptic plasticity is not clear, it is likely that presynaptic kainate receptors amplify neurotransmitter release from presynaptic terminals
through a positive feedback loop.
Nicotinic acetylcholine receptors. Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ion channels gated by
the neurotransmitter and the alkaloid acetylcholine agonist nicotine. nAChRs are mainly permeable to sodium and potassium, with
much less conductance to calcium, and are located on hippocampal pyramidal neurons as well as interneurons (Hogg et al, 2003).
Several studies have shown that nAChRs are important for learning
and memory in humans and animal models. Blockage of nAChRs
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in the hippocampus of rats results in significant memory deficits,
whereas nAChR agonists including nicotine improve certain types
of memory, such as short-term and working memory, in humans
(Ji et al, 2001; Levin et al, 2002; Seeger et al, 2004).
The molecular mechanisms underlying the effects of nAChR on
learning and memory are not fully understood. nAChR currents are
likely to take part in postsynaptic calcium signalling either directly
through their calcium component or indirectly by contributing to
postsynaptic depolarization. Notably, unlike NMDA receptors,
nAChRs are not blocked by Mg2+ at negative resting potentials;
therefore, postsynaptic nAChR activity might assist the removal of
the Mg2+ block from NMDA receptors and facilitate LTP ( Ji et al,
2001). The function of nAChRs at presynaptic terminals also seems
to be important for synaptic plasticity by enhancing neurotransmitter release (Vizi & Lendvai, 1999). Activation of nAChRs by nicotine
on presynaptic terminals in the ventral tegmental area enhances
glutamatergic inputs to dopaminergic neurons. Thus, LTP of the
excitatory synapses is induced by activation of NMDA receptors.
Both the short- and long-term effects of nicotine require the activation of presynaptic nAChRs (Mansvelder & McGehee, 2000).
Therefore, nicotine addiction might involve altered synaptic function in brain reward areas through mechanisms that are associated
with learning and memory.
GABA-A receptors. Hippocampal synapses, which use the neurotransmitter γ-aminobutyric acid (GABA), are plastic (Lamsa et al,
2005). GABA is a general inhibitory neurotransmitter, which is
sensed at GABAergic synapses by ionotropic (GABA-A) and
metabotropic (GABA-B) receptors. GABA-A ion channels consist
of five subunits forming a central pore that is permeable to negatively charged chloride ions (Cl–; Baumann et al, 2001). Cl– influx
through GABA-A receptors hyperpolarizes mature postsynaptic
neurons expressing appropriate Cl– transporters and inhibits
synaptic transmission. These inhibitory postsynaptic currents are
subject to both LTP and LTD in rat cerebellar neurons (Ouardouz &
Sastry, 2006). Interestingly, a specific subtype of GABA-A receptors
containing the α5-subunit localizes primarily in the CA1–CA3
fields of the hippocampus (Collinson et al, 2002). Mice lacking this
subunit show increased spatial learning capacity together with
attenuated inhibitory postsynaptic currents, suggesting that GABA-A
activity in the hippocampus modulates synaptic plasticity.
Repeated exposure of rats to cocaine reduces the amplitude of
GABA-A-mediated synaptic currents and increases the probability of
spike initiation in dopaminergic neurons of the ventral tegmental
area (Liu et al, 2005). In turn, dopamine neurons of the ventral
tegmental area become highly susceptible to the induction of LTP by
correlated pre- and postsynaptic activity. This cocaine-induced
enhancement of synaptic plasticity might be important for the formation of drug-associated memories. In addition, GABA-A-mediated
inhibition of dorsolateral prefrontal cortex neurons in monkeys
seems to be important for the processes underlying spatial working
memory (Rao et al, 2000).
Voltage-gated calcium channels
Voltage-gated calcium channels (VGCCs) are a diverse group of
heteromultimeric ion channels that respond to changes in membrane
potential. VGCCs are further classified into six classes—L-, N-, P-, Q-,
R- and T-type—according to their sensitivity to pharmacological
blocks, single-channel conductance kinetics and voltage dependence
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Ion channels at the synapse
G. Voglis & N. Tavernarakis
(Reuter, 1996). T-type channels have a low-voltage threshold for activation, whereas L-, N-, P-, Q- and R-type are high-voltage thresholdactivated channels. VGCCs have key roles in signal transduction
between neurons and several studies implicate specific types in
various forms of synaptic plasticity (Fig 2).
L-type ion channels are required for LTP at synapses between
mossy fibres and CA3 pyramidal neurons. This type of LTP does not
depend on NMDA receptors and involves postsynaptic calcium
influx carried by L-type VGCCs (Kapur et al, 1998). Studies of
synaptic transmission between the basolateral amygdala and the
hippocampal dentate gyrus have established a similar role for
L-type calcium channels in the induction of LTP (Niikura et al,
2004). Consistent with these observations, the administration of
nimodipine—an L-type calcium channel antagonist—abolishes LTP
and impairs fear conditioning in mice (Shinnick-Gallagher et al,
2003). Interestingly, calcium currents through L-type VGCCs in
CA1 neurons of the hippocampus increase during ageing in rats,
which is accompanied by a marked decline in learning and memory
faculties. Chronic nimodipine treatment ameliorates memory loss,
suggesting that excessive calcium influx through L-type calcium
channels impairs learning and memory (Veng et al, 2003). It is
intriguing that patients with Alzheimer’s disease show higher L-type
VGCC expression in the hippocampus compared with healthy individuals (Coon et al, 1999). This link suggests that aberrant L-type
calcium channel levels might contribute to memory shortcomings
in Alzheimer’s patients.
Other VGCCs implicated in synaptic plasticity include N-, P-,
Q- and R-type calcium channels (Wu et al, 1999). These channels
influence neurotransmitter release in the central nervous system.
P- and Q-type calcium channels are more effective than N- or Rtype channels at triggering neurotransmitter release, probably
because the latter are localized further from release sites (Wu
et al, 1999). Therefore, modulation of P- and Q-type calcium
channel conductance provides a mechanism for fine-tuning
synaptic transmitter release. Nevertheless, R-type channels seem
to carry almost one-third of the total calcium current at presynaptic terminals during a presynaptic action potential (Wu et al,
1998). Such an influx of calcium is an important component of
certain forms of synaptic plasticity; for example, the induction of
LTP at synapses between mossy fibres and CA3 hippocampal neurons requires a rise in presynaptic calcium but is independent of
postsynaptic calcium currents. R-type calcium channel activity is
involved in the induction of LTP in these synapses but is not
required for fast neurotransmitter release induced by single action
potentials (Dietrich et al, 2003).
Potassium channels
Potassium channels are the most diverse group of ion channels.
Specific potassium channels, gated by intracellular calcium elevation,
have been associated with synaptic plasticity (Fig 2).
Small-conductance calcium-activated potassium channels
(SKs) are widely distributed in the nervous system and are
involved in shaping neuronal responses to synaptic stimulation
(Bond et al, 2005). In hippocampal CA1 neurons, SKs contribute
to the after hyperpolarization and modulate neuronal excitability.
By allowing potassium efflux after their activation, SKs have the
capacity to quench postsynaptic potentials (Faber et al, 2005). In
turn, repolarization of the postsynaptic membrane favours NMDA
receptor obstruction by Mg2+ ions, which limits further calcium
©2006 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION
Presynaptic neuron
BK ion
channel
K+
Synaptic
vesicle
L-type
VGCC
Glutamate
Ca2+
Na+
Voltage induced
Mg2+ removal
Ca2+
Ca2+
NMDA
receptor
P
L-type
VGCC
K
+
Synaptic
cleft
SK ion
channel
Depolarization
Postsynaptic neuron
Fig 2 | Contribution of voltage-gated calcium channels and potassium channels
to synaptic plasticity. Voltage-gated calcium channels may function at both
pre- and postsynaptic terminals to allow calcium influx that either augments
neurotransmitter release at the presynaptic terminal or contributes to
postsynaptic neuron depolarization. Excessive calcium influx at postsynaptic
termini might impair long-term potentiation. Large-conductance calciumactivated potassium channels at presynaptic terminals and small-conductance
calcium-activated potassium channels at postsynaptic terminals quench
membrane depolarization by allowing potassium efflux, which facilitates
neuron repolarization. BK, large-conductance calcium-activated potassium
channel; NMDA, N-methyl D-aspartate; SK, small-conductance calciumactivated potassium channel; VGCC, voltage-gated calcium channel.
influx. Thus, SKs are part of a negative feedback loop that attenuates
synaptic transmission (Ngo-Anh et al, 2005). Indeed, blockage of
SKs enhances LTP in the hippocampus and the lateral amygdala,
whereas SK overexpression diminishes LTP and impairs learning
behaviours such as spatial learning and fear conditioning
(Hammond et al, 2006).
Large-conductance, calcium-activated potassium channels (BKs)
also influence synaptic plasticity. These channels are regulated by
both calcium and voltage and are localized at presynaptic terminals throughout the nervous system (Hu et al, 2001). Inactivation of
BKs increases the probability of neurotransmitter release at synapses
between CA3 neurons of the hippocampus (Raffaelli et al, 2004).
Similar observations suggest that BKs control synaptic transmission
by shunting presynaptic potentials generated by calcium influx,
which is required for neurotransmitter release. Mice lacking BKs are
abnormal in their conditioned eye-blink reflex and in their motor
coordination during locomotion, which indicate cerebellar learning deficiency (Sausbier et al, 2004). Cerebellar Purkinje neurons
from these animals show reduced spontaneous discharge activity
owing to depolarization-induced inactivation of the action-potential
mechanism. Similar effects on learning behaviours have been
observed in Drosophila, in which mutations in BKs slow habituation
(Engel & Wu, 1998). Thus, BKs might provide negative feedback
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that moderates signalling through the synapse at the presynaptic
side, under conditions of excessive depolarization and accumulation
of intracellular calcium.
Concluding remarks and outlook
Considerable progress towards deciphering the molecular mechanisms of neuronal plasticity has been accomplished in recent years.
The modulation of synaptic communication has emerged as a
major mechanism underlying information storage and retrieval by
the nervous system. Synaptic ion channels have a fundamental role
in this process by facilitating and fine-tuning synaptic transmission.
However, in spite of these exciting advances, many challenges still
remain. We do not fully understand how synaptic ion channels are
regulated to influence neuronal communication. Although many
signalling pathways that control synaptic ion channel conductance
are known, it is not clear how information processing by clusters of
neurons engages these pathways to accomplish memory storage
and retrieval. Even less clear are the mechanisms that support the
maintenance of intricate memory traces in neuronal networks. The
processes responsible for the time-dependent decay of memory
traces are also poorly understood.
Non-synaptic forms of neuronal plasticity impose an additional
layer of complexity. For example, in spontaneously firing neurons in
the medial vestibular nucleus, CaMKII positively regulates calciumactivated potassium channels to maintain low levels of intrinsic
excitability (Nelson et al, 2005). These neurons have a key role in
motor learning in the vestibulo-ocular reflex and have capacity for
firing rate potentiation (FRP), a form of plasticity in which synaptic
inhibition triggers long-lasting increases in intrinsic excitability. In
this system, CaMKII acts as a molecular switch, converting brief
changes in synaptic activity or calcium influx into long-term
changes in non-synaptic ion channel activity (Lisman et al, 2002). A
decrease in CaMKII activity is both necessary and sufficient to
induce FRP (Nelson et al, 2005).
Specific, non-synaptic voltage-gated potassium (Kv) channels are
important for controlling neuron membrane electrical excitability
and are localized to axons, somata and dendrites. During the early
phase of LTP at postsynaptic terminals of CA1 hippocampal neurons,
calcium entering through AMPA and NMDA receptors activates
CaMKII, which phosphorylates Kv channels and increases neuronal
excitability (Sweatt, 2001). Similarly, specific mitogen-activated protein kinases and protein kinase A are stimulated by elevated levels of
cAMP as a result of calcium entry and subsequent activation of
adenylyl cyclase-1, and also seem to phosphorylate Kv channels
(Morozov et al, 2003). Deletion of the auxiliary Kvβ1.1 subunit in
CA1 hippocampal neurons results in increased neuronal excitability
and improved LTP induction in aged mice. These mice consistently
performed better than wild-type mice in learning and memory tests
(Murphy et al, 2004).
Hyperpolarization-activated, cyclic nucleotide-gated (HCN, Ih)
ion channels are voltage-dependent, nonselective, cation channels that are widely expressed in the nervous system and localize
to diverse pre- and postsynaptic terminals (Pape, 1996; Robinson
& Siegelbaum, 2003). Neuronal HCN channels contribute to fundamental physiological processes such as the regulation of membrane potential, the integration of synaptic input to neurons and
the rhythmicity of various brain regions (Robinson & Siegelbaum,
2003). HCN channels are modulated by both voltage and cAMP. In
the absence of cAMP, HCN channels open when the intracellular
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Ion channels at the synapse
G. Voglis & N. Tavernarakis
potential becomes more negative (hyperpolarization). cAMP
binding enhances the rate of activation of lh and promotes a larger
current. HCN channels are ideally suited for modulating neurotransmitter release and effects because of their synaptic localization. Although they seem to have diverse functions in neuronal regulation, their contribution to synaptic transmission and plasticity is
not fully understood. HCN channels in distal dendrites of pyramidal cells in the hippocampus are likely to dampen postsynaptic
potentials that might otherwise trigger synaptic plasticity. Indeed,
deletion of HCN1, which encodes an HCN ion channel subunit
that contributes to Ih currents in hippocampal CA1 neurons,
enhances LTP and hippocampal-dependent learning and memory
(Nolan et al, 2004).
Uncovering the mechanisms that modulate neuronal communication through synaptic transmission to support information storage
and retrieval by clusters of neurons is a central challenge for the
future. The availability of new tools, such as non-invasive optical
recording methods that allow real-time monitoring of neuronal
activity in vivo, will facilitate the further molecular characterization
of neuronal plasticity. The ultimate goal is to visualize synaptic activity and the formation of memory traces. Novel, fluorescent probes
and microscopy techniques hold promise for significant advances
towards this goal in the near future (Filippidis et al, 2005; Helmchen
et al, 2001; Okumoto et al, 2005; Peleg et al, 1999). Indeed, modern
genetically encoded fluorescent protein reporters can be targeted to
specific neurons, allowing imaging of neuronal activity at singlesynapse resolution (Bozza et al, 2004; Yuste et al, 2000). Combining
this technology with genetic analyses in model organisms will provide a powerful platform for the comprehensive dissection of synaptic ion channel contributions to learning and memory. Such holistic
approaches will ultimately bring together all pieces of the puzzle,
exposing the elaborate links between genes, neurons and behaviour.
ACKNOWLEDGEMENTS
We acknowledge the contributions of numerous investigators that we could
not include in this review owing to space limitations. Work in the authors’
laboratory is funded by grants from the European Molecular Biology
Organization, the European Union 6th Framework Programme and the
Institute of Molecular Biology and Biotechnology (IMBB). N.T. is an EMBO
Young Investigator.
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